Process for the production of amorphous atorvastatin calcium

ABSTRACT

A novel process of the preparation of amorphous atorvastatin calcium starting from a compound of Formula (II).

FIELD OF THE INVENTION

The present invention relates to a novel process for the production ofamorphous atorvastatin calcium. Particularly, the present inventionrelates to a novel process for the production of amorphous atorvastatincalcium from(6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-1-yl]-ethyl}-2-phenyl-[1,3,2]dioxaborinan-4-yl)-aceticacid tert-butyl ester.

BACKGROUND OF THE INVENTION

Atorvastatin calcium is known by synonyms like [R—(R*,R*)]-2-(4-fluorophenyl)-□□,6-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyy-1h-pyrrole-1-heptanoic acid hemicalcium salt; (□R,□R)-2-(4-fluorophenyl)-□□-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-,1H-Pyrrole-1-heptanoic acid hemicalcium salt;[R—(R*,R*)]-2-(4-fluorophenyl)-□.□-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-,1H-Pyrrole-1-heptanoic acid hemicalcium salt or(□R,□R)-2-(p-Fluorophenyl)-□□-dihydroxy-5-isopropyl-3-phenyl-4-(phenylcarbamoyl)pyrrole-1-heptanoicacid hemicalcium salt.

Hemicalcium salt of[R—(R*,R*)]-2-(4-fluorophenyl)-□□-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-,1H-Pyrrole-1-heptanoic acid, a synthetic HMG-CoA reductase inhibitor, isused for the treatment of hyperlipidemia and hypercholesterolemia, bothof which are risk factors for arteriosclerosis and coronary heartdisease. Open dihydroxy carboxylic acid, lactone and various salt formsof[R—(R*,R*)]-2-(4-fluorophenyl)-□□-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-,1H-Pyrrole-1-heptanoic acid have been synthesized.

U.S. Pat. No. 5,273,995, describes that[R—(R*,R*)]-2-(4-fluorophenyl)-□□-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-,1H-Pyrrole-1-heptanoic acid has surprising inhibition of thebiosynthesis of cholesterol. Calcium salt of[R—(R*,R*)]-2-(4-fluorophenyl)-□□-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-,1H-Pyrrole-1-heptanoic acid (2:1) which is more suited to formulationsand has been recommended as a drug.

U.S. Pat. Nos. 5,003,080; 5,097,045; 5,103,024; 5,124,482; 5,149,837;5,155,251; 5,216,174; 5,245,047; 5,248,793; 5,273,995; 5,280,126;5,298,627; 5,342,952; 5,385,929; 5,397,792; European Patent 409,281; andWO 89/07598 describe various processes and key intermediates forpreparing atorvastatin.

WO 97/03958 and WO 97/03959 disclose novel crystalline forms ofatorvastatin calcium designated as Form I, Form II, Form III and Form IVand method for their preparation which provide more favorable filtrationand drying characteristics.

WO 97/03960 and U.S. Pat. No. 6,087,511 describe the procedures forconverting the crystalline form of atorvastatin calcium to the amorphousform. The process disclosed therein involve dissolving form Iatorvastatin calcium in a non-hydroxylic solvent like tetrahydrofuran ora mixture of tetrahydrofuran and toluene.

WO 00/71116 describes the procedure for converting the crystallineform-I by dissolving it in a non-hydroxylic solvent like tetrahydrofuranand precipitating amorphous atorvastatin calcium by the addition ofnonpolar hydrocarbon solvents like, n-hexane, cyclohexane or n-heptane.The process described in the above mentioned patent involves dissolvingthe crystalline atorvastatin (form-I) in a non hydroxylic solvent liketetrahydrofuran or mixtures of tetrahydrofuran and toluene, followed byremoval of the solvents under high temperature (about 90° C.) and highvacuum (about 5 mm). This process may not suitable on a large scale asthe conditions used for drying may lead to degradation of the product.

Many of the process disclosed in the above patents does not produceatorvastatin calcium in its amorphous form consistently. Often a mixtureof crystalline and amorphous form is obtained which is not suitable forfiltration and drying and therefore not a desirable process forlarge-scale production.

It is the object of the present invention to provide a novel process forthe preparation of amorphous atorvastatin calcium, which is unique withrespect to its simplicity, cost effectiveness and scalability.

SUMMARY OF THE INVENTION

The instant invention relates to a novel process of the preparation ofamorphous atorvastatin calcium.

The novel process of instant invention comprises conversion of compoundof Formula II

to atorvastatin calcium (Formula I).

DETAILED DESCRIPTION OF THE INVENTION

The instant process for the preparation of amorphous form of compound ofFormula I from a compound of Formula II comprising:

-   -   (a) adding aqueous NaOH to the compound of Formula II to get a        sodium salt,    -   (b) dissolving the wet sodium salt in ethyl acetate,    -   (c) addition of calcium acetate followed by stirring,    -   (d) collecting the organic layer and concentrating to get a        residue,    -   (e) drying the residue to get amorphous compound of Formula I.

The process where calcium acetate in step (c) is calcium acetate isoptionally substituted with calcium chloride.

The process where the amorphous compound of Formula I is vacuum dried.

The novel process of instant invention has following advantages:

-   1. De-protection of boronate ester and cleavage of tert-butyl ester    and formation of calcium salt is done easily in one pot.-   2. Simple procedure involving inexpensive Calcium Acetate.-   3. An inexpensive method.-   4. The process is industrially scaleable.-   5. Amorphous atorvastatin calcium is obtained directly without    isolation of crude material.

The present invention will now be illustrated by the following examples,which are not intended to limit the effective scope of the claims.Consequently, any variations of the invention described above are not tobe regarded as departure from the spirit and scope of the invention asclaimed. The present invention has been described in terms of itsspecific embodiments and various modifications and equivalents will beapparent to those skilled in the art and are intended to be includedwithin the scope of present invention.

EXAMPLES Example I

(6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-1-yl]-ethyl}-2-phenyl-[1,3,2]dioxaborinan-4-yl)-aceticacid tert-butyl ester (compound of Formula II, 500 g, 0.7 mol) wasdissolved in THF (4 L) and degassed with nitrogen gas for 30 minutes. Asolution of sodium hydroxide (142 g) in water (3.57 L) was added to theabove solution and refluxed for 2 hours. The reaction mixture wasconcentrated under vacuum to remove solvent and water (7.5 L) was addedfollowed by MTBE (2.5 L). After separating layers, aqueous was keptunder vacuum for 1 hour and the solution was allowed to stand for 12 hrsat room temperature. The precipitate formed (sodium salt ofatorvastatin) was filtered and dissolved in ethyl acetate (3.5 L). Tothe clear organic layer, a solution of calcium acetate (99.4 g) in water(2 L) was added and stirred at 40-45° C. The layers were separated andorganic layer was washed with water (5×5 L). The organic layer wasevaporated and residue was dried under vacuum to get AtorvastatinCalcium amorphous.

Yield: 380 g. Example II

(6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-1-yl]-ethyl}-2-phenyl-[1,3,2]dioxaborinan-4-yl)-aceticacid tert-butyl ester (compound of Formula II, 10 kg, 14.82 mol),compound of Formula II, was dissolved in THF (80 L) and degassed withnitrogen gas for 30 minutes. A solution of sodium hydroxide (2.84 kg) inwater (72 L) was added to the above solution and refluxed for 4 hours.The reaction mixture was concentrated under vacuum to remove solvent andwater (150 L) was added followed by MTBE (50 L). After separatinglayers, aqueous was kept under vacuum for 3 hours and the solution wasallowed to stand for 12 hrs at 25-28° C. The precipitate formed (sodiumsalt of atorvastatin) was filtered and dissolved in ethyl acetate (70 L)To the clear organic layer, a solution of calcium acetate (2 kg) inwater (40 L) was added and stirred at 40-45° C. The layers wereseparated and organic layer was washed with water (5×100 L). The organiclayer was evaporated and residue was dried under vacuum to getAtorvastatin Calcium amorphous.

Yield: 7.2 kg Example III

(6-{2-[2-(4-Fluoro-phenyl)-5-isopropyl-3-phenyl-4-phenylcarbamoyl-pyrrolidin-1-yl]-ethyl}-2-phenyl-[1,3,2]dioxaborinan-4-yl)-aceticacid tert-butyl ester (compound of Formula II, 500 g, 0.7 mol) wasdissolved in THF (4 L) and degassed with nitrogen gas for 30 minutes. Asolution of sodium hydroxide (142 g) in water (3.57 L) was added to theabove solution and refluxed for 2 hours. The reaction mixture wasconcentrated under vacuum to remove solvent and water (7.5 L) was addedfollowed by MTBE (2.5 L). After separating layers, aqueous was keptunder vacuum for 1 hour and the solution was allowed to stand for 12 hrsat room temperature. The precipitate formed (sodium salt ofatorvastatin) was filtered and dissolved in ethyl acetate (3.5 L). Tothe clear organic layer, a solution of calcium chloride (60 g) in water(2 L) was added and stirred at 40-45° C. The layers were separated andorganic layer was washed with water (5×5 L). The organic layer wasevaporated and residue was dried under vacuum to get AtorvastatinCalcium amorphous.

Yield: 350 g.

1. A novel process for the preparation of amorphous form of compound ofFormula I from a compound of Formula II comprising:

(a) adding aqueous NaOH to the compound of Formula II to get a sodiumsalt, (b) dissolving the wet sodium salt in ethyl acetate, (c) additionof calcium acetate followed by stirring, (d) collecting the organiclayer and concentrating to get a residue, (e) drying the residue to getamorphous compound of Formula I.
 2. A process as in claim 1, whereincalcium acetate in step (c) is calcium acetate is optionally substitutedwith calcium chloride.
 3. A process as in claim 1, wherein the amorphouscompound of Formula I is vacuum dried.
 4. A process as in claim 1,wherein sodium salt in step (b) is optionally dried and furtherprocessed.